tbuckley/cabot-search huggingface dataset:
Abstract 3679: DNAJB1-PRKACA fusion in fibrolamellar hepatocellular carcinoma induces glutamine addiction and an immunosuppressive tumor microenvironment
Authors: Zeal Kamdar, Tamara Lopez-Vidal, Kathryn Howe, Kabeer Munjal, Ali Saeed, Daniel Zabransky, Daniel Shu, Gabriella Longway, Emma Kartalia, James Leatherman, Aditya Mohan, Pratik Khare, Cissy Zhang, Anne Le, Erika Pearce, Mark Furth, Marina Baretti, Robert Leone, Elizabeth Jaffee, Mark Yarchoan
Journal: Cancer Research (2023)

Abstract Fibrolamellar hepatocellular carcinoma (FLC) is a rare and often lethal form of liver cancer that primarily affects children and young adults. A fusion between DNAJB1, a heat shock chaperone protein, and PRKACA, the catalytic domain of protein kinase A (PKA) has been identified as a signature genomic event in FLC, but the effect of this fusion on the tumor immune microenvironment is not understood. We created an orthotopic, syngeneic model of FLC (TIBx-FLC) by inducing the DNAJB1-PRKACA fusion in a murine hepatoblastoma-derived cell line (TIBx). CD8 T cells isolated from TIBx-FLC tumors demonstrated markedly impaired activation as compared to CD8 T cells isolated from control TIBx tumors. We investigated metabolic programming as a potential mechanism for DNAJB1-PRKACA immunosuppression in FLC. Labeled glucose metabolomics performed on TIBx-FLC and TIBx tumor cells demonstrated a metabolic shift away from aerobic metabolism to an increased glucose contribution towards the hexosamine biosynthetic pathway and purine synthesis, which requires glutamine as a nitrogen source. As compared to the parental TIBx cell line, the TIBx-FLC cell line demonstrated high sensitivity to glutamine antagonism in vitro, consistent with glutamine addiction. Systemic treatment of BALB/c mice bearing TIBx-FLC tumors with JHU-083, a glutamine antagonist, in combination with immune checkpoint inhibitor therapy enhanced survival as compared to vehicle or monotherapy. These data identify altered glutamine metabolism as a target in FLC, and may provide an explanation for immune suppression seen in the FLC tumor microenvironment. Citation Format: Zeal Kamdar, Tamara Lopez-Vidal, Kathryn Howe, Kabeer Munjal, Ali Saeed, Daniel Zabransky, Daniel Shu, Gabriella Longway, Emma Kartalia, James Leatherman, Aditya Mohan, Pratik Khare, Cissy Zhang, Anne Le, Erika Pearce, Mark Furth, Marina Baretti, Robert Leone, Elizabeth Jaffee, Mark Yarchoan. DNAJB1-PRKACA fusion in fibrolamellar hepatocellular carcinoma induces glutamine addiction and an immunosuppressive tumor microenvironment. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3679.
Abstract 3721: The C1 domain of capicua has functional importance in human CIC-DUX4
Authors: Cuyler Luck, Kyle A. Jacobs, Ross A. Okimoto
Journal: Cancer Research (2023)

Abstract Genomic rearrangements between the HMG-box family transcriptional repressor capicua (CIC) and multiple partner genes result in fusion oncoproteins that activate transcription to drive sarcoma growth and progression. In the case of CIC-DUX4, the most common CIC-rearranged fusion oncoprotein, the fusion often retains over 90% of the wild type CIC protein structure including the HMG box and C-terminal C1 domain. Structure-function studies in Drosophila have suggested that the C1 domain of CIC, a non-HMG box DNA binding domain, is important for the transactivating capacity of a synthetic fly-human CIC-DUX4. Consistent with these findings, we performed a retrospective analysis of over 70 breakpoints described from CIC-DUX4 human derived tumors, which revealed that the C1 domain is structurally conserved within the context of the CIC-DUX4 fusion. To further understand the functional role of the C1 domain in human CIC-DUX4 we generated human CIC-DUX4 C1 domain and HMG-box deletion (alone or in combination) mutant constructs and performed a series of studies to test the functional impact on CIC-DUX4 protein levels, subcellular localization, and transcriptional activity. Through these analyses we have found that deletion of the C1 domain does not impact CIC-DUX4 oncoprotein expression or localization but does dramatically reduce target gene expression. In ongoing in vivo studies, we aim to evaluate the significance of the C1 domain in inducing CIC-DUX4 driven tumorigenesis. Collectively, our findings validate the functional importance of the C1 domain in human CIC-DUX4 and to our knowledge provide the first harmonized analysis of breakpoint locations in CIC-rearranged sarcoma. Citation Format: Cuyler Luck, Kyle A. Jacobs, Ross A. Okimoto. The C1 domain of capicua has functional importance in human CIC-DUX4. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3721.
Abstract 3707: UXS1 is a synthetic lethal target in cancer
Authors: Michelle Patricia Cicchini, Shuzhen Wu, Yang Peng, Yanhua Rao
Journal: Cancer Research (2023)

Abstract Studies presented here were conducted to validate UXS1 as a synthetic lethal target in UGDHhigh expressing cancer. In vitro and in vivo knockout studies were used to investigate the role of UXS1 in UGDH-high cancers. UXS1 has been validated as a synthetic lethal target in cancer cell lines highly expressing UGDH in vitro by CRISPR-mediated knockout of UXS1 in a panel of lung cancer cell lines. In addition to UGDH expression predicting UXS1 dependency, we have shown UGDH overexpression functional drives UXS1 dependency, such that knockout of UGDH rescues cellular growth defects seen with UXS1-knockout alone. Furthermore, catalytic activity of UXS1 was shown to be required, as wildtype but not catalytic deficient UXS1 was able to rescue cellular growth defects seen with endogenous UXS1 knockout in UGDH-high cancer cell lines. Together this data suggests that dysregulation of some metabolite(s) is driven by high expression of UGDH when knockout of UXS1 prevents normal pathway flux of UDP-Glucuronic Acid (UDP-GA) to be converted to UDP-Xylose (UDP-X), leading to the synthetic lethal effect observed as impaired cellular growth. To validate UXS1 as a target in vivo, an inducible genetic knockout system to knockout UXS1 showed impaired tumor growth, but no tumor regression. Sanger sequencing of UXS1 knockout efficiency at different time course suggested a slow and incomplete dropout of the UXS1-KO cells in vivo. Although in vitro efforts have shown UXS1 to a synthetic lethal target, the failure to induce a robust in vivo effect of UXS1 knockout have casted doubts on the promise of UXS1 being an effective target for the proposed indication. Citation Format: Michelle Patricia Cicchini, Shuzhen Wu, Yang Peng, Yanhua Rao. UXS1 is a synthetic lethal target in cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3707.
Abstract 3747: Transcribed ultra-conserved regions (TUCRs): A first computational and molecular characterization of an understudied class of molecules in gliomas
Authors: Myron K. Gibert, Bilhan Chagari, Christian Roig-Laboy, Aditya Sarkar, Roger Abounader
Journal: Cancer Research (2023)

Abstract Gliomas are the most common malignant primary brain tumors. Particularly, glioblastoma (GBM) is the most common and deadliest malignant brain tumor. Most glioma research has focused on protein-coding genes and much less on the non-coding transcripts that make up 98% of cellular RNA. Transcribed Ultra-Conserved Regions (TUCRs) represent an understudied class of molecules that are found highly conserved across multiple species, including 100% conservation in mouse and rat genomes. These 481 transcripts are highly resistant to variation and are commonly deregulated in cancer, which suggests regulatory and functional importance when considered along with their high degree of conservation. We performed the first-ever characterization of TUCRs in gliomas in silico. Using an elaborate workflow, we annotated and identified TUCRs that are deregulated in GBM and low-grade glioma (LGG), associated with patient outcomes, and predicted their function in glioma initiation and progression. Most TUCRs were long non-coding RNAs. Of these, we investigated the most highly upregulated intergenic TUCR, uc.110, in vitro and in vivo in glioma cell lines. Knockdown of uc.110 expression via siRNA resulted in reduced glioma cell accumulation, viability, and invasion in vitro while reducing tumor volume and increasing overall survival in vivo. Concurrent lentiviral overexpression of uc.110 partially rescued wild-type expression, accumulation, viability, and invasion in vitro. Therefore, it is likely that this TUCR is functioning as an oncogene within the context of GBM. Our study represents the first comprehensive characterization of TUCRs in gliomas and can serve as a foundation and framework for similar studies in gliomas and other cancers. Citation Format: Myron K. Gibert, Bilhan Chagari, Christian Roig-Laboy, Aditya Sarkar, Roger Abounader. Transcribed ultra-conserved regions (TUCRs): A first computational and molecular characterization of an understudied class of molecules in gliomas. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3747.
Abstract 1078: Sotorasib and metformin combination enhances cytotoxicity and apoptosis in KRAS mutant lung cancer cell lines
Authors: Norma Yanet Hernandez-Pedro, Pedro Barrios-Bernal, José Lucio-Lozada, Maritza Ramos-Ramirez, Oscar Arrieta
Journal: Cancer Research (2023)

Abstract KRAS is the most frequently mutated oncogene in lung adenocarcinoma (50%) and it is associated with a poor response to antineoplastic treatments, as well as poorer survival rates. KRAS activates the MAPK pathway, promoting cell survival and increasing protein synthesis. Novel inhibitors of KRAS G12C mutation (sotorasib) have demonstrated short-lasting responses due to resistance mediated by the AKT-mTOR-P70S6K pathway. In this context, metformin is a promising candidate to avoid this inconvenience by inhibiting mTOR and P70S6K. Therefore, this project aimed to explore the effects of the combination of sotorasib and metformin on cytotoxicity, apoptosis, and the activity of the mTOR pathway in lung cancer cell lines with or without KRAS mutations. Methods: We performed dose-effect curves to determine the IC50 concentration of sotorasib, and IC10 of metformin. Then, these doses were used to treat lung cancer cell lines A549 (KRAS G12S), H522 (without KRAS), and H23 (KRAS G12C). Cellular cytotoxicity was evaluated by MTT assay, apoptosis induction through flow cytometry with Annexin V and 7AAD, and the activity of P70S6K and AKT proteins by western blot. Main outcomes and measures: cell survival, apoptosis, expression, and phosphorylation of intermediaries belonging to the mTOR pathway. Results: The combined treatment showed a synergic effect on cytotoxicity, increased apoptosis induction, and notable inhibition of AKT and P70S6K1 proteins, compared to sotorasib alone or to control groups in all the cell lines, but predominantly in KRAS-mutated cells (H23 and A549). Conclusions: The combination of metformin with sotorasib showed synergic effects on cytotoxicity, increased apoptosis induction, and a remarkable inhibition of downstream proteins involved in the signaling of growth factor receptors in all tested cells. Moreover, these results suggest a sensitizing effect of metformin to sotorasib treatment in cells without KRAS mutations, such as H522. Citation Format: Norma Yanet Hernandez-Pedro, Pedro Barrios-Bernal, José Lucio-Lozada, Maritza Ramos-Ramirez, Oscar Arrieta. Sotorasib and metformin combination enhances cytotoxicity and apoptosis in KRAS mutant lung cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1078.
Abstract 889: The efficacy and safety of PD-L1-specific CAR-T in advanced gastric cancer
Authors: Hye-Seong Park, Eun-Ji Choi, Jae-In Yu, Kyung-Sik Lee, Yeo-Jin Lim, Se-Ryeong Choi, Yoonjoo Choi, Bum Chan Park, Jae Eun Park, Mihwa Kim, Je-Jung Lee, Joon Haeng Rhee
Journal: Cancer Research (2023)

Abstract [Purpose] Heterogeneity and the tumor microenvironment are major obstacles to overcoming incurable advanced gastric cancer (AGC). Although Epstein-Barr virus-positive and microsatellite instability subtypes can be detected early and properly treated, they are rare in AGC. In this regard, recent combinational therapy of immune checkpoint inhibitors (ICIs) such as PD-1/PD-L1 inhibitors and other various therapeutics has been tried, but there are clinically limited doses and drug resistance. We hypothesized that CAR-T targeting PD-L1, the common tumor-associated antigen (TAA), which expresses in most advanced cancer cells, would make a significant breakthrough in curing a solid tumor. This study aimed to evaluate the killing effects of anti-PD-L1 CAR-T against gastric cancer cell lines. Removal of PD-L1-expressing cells in the AGC TME will improve the clinical outcomes of current therapies. [Results] We constructed a second-generation PD-L1 CAR lentiviral vector targeting PD-L1, which has an intermediate affinity with PD-L1 in solid tumor TME. As the secondary signaling motif, CD28 was chosen and tested along with the CD3 zeta chain. The effector CAR-T, named Vax-CAR-T, specifically recognized the PD-L1-expressing AGC cell line, SNU638, and exhibited rapid and robust cytotoxic activity in vitro. When compared to untransduced T cells, the level of the CD25 activation marker was higher in Vax-CAR-T cells. Besides, the inhibitory markers of Tim3 and LAG3 were expressed even higher than the untransduced. Despite high Tim3 and LAG3 expression in the final manufacturing process, Vax-CAR-T cells significantly suppressed tumor growth in both bigger (&amp;gt;95mm3) and smaller (≤50mm3) AGC xenograft NSG mouse models. More importantly, Vax-CAR-T-treated mice have well tolerated the CAR-T therapy with no significant adverse events during the CRS monitoring period, 2 weeks after Vax-CAR-T injection and have gradually recovered weight gains 5 days after CAR-T cell injection. [Conclusion] We believe that a new autologous CAR-T targeting PD-L1 could be a promising new tool for removing heterogeneous solid tumors in TME, which would be a significant step forward in improving current conventional and immunotherapeutic strategies. Citation Format: Hye-Seong Park, Eun-Ji Choi, Jae-In Yu, Kyung-Sik Lee, Yeo-Jin Lim, Se-Ryeong Choi, Yoonjoo Choi, Bum Chan Park, Jae Eun Park, Mihwa Kim, Je-Jung Lee, Joon Haeng Rhee. The efficacy and safety of PD-L1-specific CAR-T in advanced gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 889.
Abstract 3708: Platelet-derived microparticles modulate breast cancer malignant processes
Authors: Vanessa Veilleux, Nicolas Pichaud, Luc H. Boudreau, Gilles A. Robichaud
Journal: Cancer Research (2023)

Abstract Breast cancer is one of the leading causes of morbidity and mortality among women, where metastasis accounts for the majority of deaths associated with this disease. Thus, the potential to effectively target tumor malignancy offers hope to mitigate disease progression and improve patient outcomes. It is well established that platelets promote multiple processes of metastasis cascade. Recently, platelets have received new attention for their impact in cancer through the production of platelet-derived microparticles (PMPs). Interestingly, PMPs allow intercellular exchange and trafficking of bioactive material through the internalization of these vesicles into recipient cells. As a result, the delivery of the intravesicular cargo can modulate signaling and activation processes of recipient cells. We recently identified a new subpopulation of these vesicles (termed mitoMPs) containing functional mitochondria. Given the predominant role of mitochondria in cancer malignancy, we believe that mitoMPs provide an important source of foreign mitochondria to support recipient breast cancer cells in malignancy and disease progression. We therefore set out to study the impact of mitoMPs on breast cancer metabolic and phenotypic processes involved in metastasis. Technically, PMPs were generated and purified from human blood platelets and co-incubated with various breast cell models (MB231, MCF7 and MCF10A). The physiological significance of mitoMPs in breast cancer disease was then assessed using various cellular and molecular assays. We demonstrate that the level of PMP internalization is highly dependent upon the type of breast cancer recipient cells. Furthermore, we show that the cargo of mitoMPs (notably mitochondria) is biologically active where recipient breast cancer cells acquired mitochondria-dependent functions, such as increased oxygen consumption rates and intracellular ATP production. Finally, we observe that mitoMPs promote malignant features such as cancer cell migration and invasion. Overall, we demonstrate that PMPs can modulate cancer cell activation and behaviour. These findings provide a better understanding of the extracellular tumor environment and the contribution of mitoMPs in supporting breast cancer cells through the metastatic landscape. The knowledge gained will further provide new avenues for therapeutic strategies in breast cancer patients. Citation Format: Vanessa Veilleux, Nicolas Pichaud, Luc H. Boudreau, Gilles A. Robichaud. Platelet-derived microparticles modulate breast cancer malignant processes. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3708.
Abstract 3709: Hyperglycemia induces metabolic reprogramming and promotes epithelial-mesenchymal transitions in pancreatic cancer: an in vitro and in vivo experiment
Authors: Zhao Liu, Hiromitsu Hayashi, Kazuki Matsumura, Yoko Ogata, Hiroki Sato, Yuta Shiraishi, Norio Uemura, Tatsunori Miyata, Takaaki Higashi, Shigeki Nakagawa, Kosuke Mima, Katsunori Imai, Hideo Baba
Journal: Cancer Research (2023)

Abstract Background: Pancreatic cancer is a serious life-threatening disease due to its highly invasive and metastatic potential. Hyperglycemia is a well-known initial symptom in patients with pancreatic ductal adenocarcinoma (PDAC). Metabolic reprogramming in cancer, described as the Warburg effect, can induce epithelial-mesenchymal transition (EMT). In this study, we elucidate the biological and clinical impact of hyperglycemia in PDAC progression. Methods: Biological impact of hyperglycemia on malignant behavior in PDAC was examined by in vitro and in vivoexperiment. Results: Hyperglycemia promoted EMT by inducing metabolic reprogramming into a glycolytic phenotype via yes-associated protein (YAP)/PDZ-binding motif (TAZ) overexpression, accompanied by GLUT1 overexpression and enhanced phosphorylation Akt in PDAC. In addition, hyperglycemia enhanced chemoresistance by upregulating ABCB1 expression, and triggered PDAC switch into pure-basal-like subtype with activated Hedgehog pathway (GLI1 high, GATA6 low expression) through YAP/TAZ overexpression. PDAC is characterized by abundant stroma that harbors tumor-promoting properties and chemoresistance. Hyperglycemia promotes production of collagen fiber-related proteins (fibronectin, fibroblast activation protein, COL1A1, and COL11A1) by stimulating YAP/TAZ expression in cancer-associated fibroblasts (CAFs). Knockdown of YAP and/or TAZ or treatment with YAP/TAZ inhibitor (K975) abolished EMT, chemoresistance, and a favorable tumor microenvironment even under hyperglycemic conditions in vitro and in vivo. Indeed, YAP/TAZ overexpression was significantly associated with worse prognostic outcomes in human PDAC patients. Conclusion: Hyperglycemia induce metabolic reprogramming into a glycolytic phenotype and promote EMT via the YAP/TAZ-Hedgehog signaling axis in PDAC. Hyperglycemia as an initial symptom may be the cause of highly invasive and metastatic potential by inducing YAP/TAZ overexpression, while YAP/TAZ could be a novel therapeutic target in PDAC patients. Citation Format: Zhao Liu, Hiromitsu Hayashi, Kazuki Matsumura, Yoko Ogata, Hiroki Sato, Yuta Shiraishi, Norio Uemura, Tatsunori Miyata, Takaaki Higashi, Shigeki Nakagawa, Kosuke Mima, Katsunori Imai, Hideo Baba. Hyperglycemia induces metabolic reprogramming and promotes epithelial-mesenchymal transitions in pancreatic cancer: an in vitro and in vivo experiment. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3709.